Abstract
ObjectiveCrizotinib can target against mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK), which has been considered as a multi-targeted tyrosine kinase inhibitor (TKI). The objective of this study was to explore the efficacy of crizotinib in advanced non-small-cell lung cancer (NSCLC) with concomitant ALK rearrangement and c-Met overexpression.MethodsTotally, 4622 advanced NSCLC patients from two institutes (3762 patients at the Guangdong Lung Cancer Institute from January 2011 to December 2016 and 860 cases at the Perking Cancer Hospital from January 2015 to December 2016) were screened for ALK rearrangement with any method of IHC, RACE-coupled PCR or FISH. C-Met expression was performed by IHC in ALK-rearranged patients, and more than 50% of cells with high staining were defined as c-Met overexpression. The efficacy of crizotinib was explored in the ALK-rearranged patients with or without c-Met overexpression.ResultsSixteen patients were identified with c-Met overexpression in 160 ALK-rearranged cases, with the incidence of 10.0% (16/160). A total of 116 ALK-rearranged patients received the treatment of crizotinib. Objective response rate (ORR) was 86.7% (13/15) in ALK-rearranged patients with c-Met overexpression and 59.4% (60/101)in those without c-Met overexpression, P = 0.041. Median PFS showed a trend of superiority in c-Met overexpression group (15.2 versus 11.0 months, P = 0.263). Median overall survival (OS) showed a significant difference for ALK-rearranged patients with c-Met overexpression group of 33.5 months with the hazard ratio (HR) of 3.2.ConclusionsC-Met overexpression co-exists with ALK rearrangement in a small population of advanced NSCLC. There may be a trend of favorable efficacy of crizotinib in such co-altered patients.
Highlights
Targeted therapy has led to a therapeutic paradigm shift in lung cancer, which brought the treatment of lung cancer into the era of precision medicine [1]
Patients characteristics A total of 4622 advanced non-small-cell lung cancer (NSCLC) patients from two institutes (3762 patients at Guangdong Lung Cancer Institute from 2011 to 2016 and 860 cases at Perking Cancer Hospital from 2015 to 2016) with complete electronic records were screened for anaplastic lymphoma kinase (ALK) gene status, of whom 282 were identified with ALK rearrangement
Sixteen patients were identified with cellular-mesenchymal-epithelial transition (c-Met) overexpression, accounted for 10.0% (16/160) of ALK-rearranged patients
Summary
Targeted therapy has led to a therapeutic paradigm shift in lung cancer, which brought the treatment of lung cancer into the era of precision medicine [1]. The activation of c-Met pathway results from gain-of-function MET mutations, MET amplification and c-Met overexpression in many solid and hematological malignancies [11, 12]. MET amplification occurred in 7.3–10.4% of patients with untreated NSCLC [13,14,15]. MET exon 14-alteration accounted for 0.9–3.0% of lung adenocarcinoma, while c-Met protein was reportedly overexpressed in about 22.2–67.2% of NSCLC and associated with poor prognosis [16,17,18,19,20,21,22,23]. Since MET amplification is rare and difficulty in the detecting method of FISH, MET IHC acts as the most robust predictor of overall survival and progression-free survival to all examined exploratory markers [24]. It is not clear that the role of c-Met overexpression plays in ALK-rearranged patients
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